Project Summary/Abstract This resubmission will explore a potential pathophysiologic link between obesity, HDL function and thrombosis by examining how two types of bariatric surgery ? Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) ? affect (1) platelet function and gene expression in morbidly obese individuals, and (2) the in vitro effect of HDL on platelet aggregation and platelet precursor gene expression. It will also examine changes in HDL composition as mechanisms underlying the differential effects of RYGB and SG on HDL function in obesity. Candidate: This application will support Dr. Sean Heffron's career development into an independent translational cardiovascular (CV) physician-scientist in the field of obesity and cardiovascular disease (CVD). Dr. Heffron's career goal is to better understand how obesity elevates CVD risk, and how CVD risk is modulated by different weight loss techniques, to support the development of effective therapies to alleviate this risk. His proposed training plan focuses on 3 areas: (1) translational laboratory techniques; (2) research methods & design; and (3) statistical analysis & biomedical informatics. Environment: NYU School of Medicine is a national leader in research and one of the top 20 medical schools in NIH funding. The Division of Cardiology is a top-ranked division nationally, with the largest research budget in the NYU Department of Medicine. Research: Nearly 90 million Americans are obese and at increased risk for atherosclerosis, thrombosis and CV mortality. Impaired HDL function in obesity may contribute to this increased risk. Dr. Heffron's preliminary data indicate that HDL function in cholesterol efflux increases after SG, but decreases following RYGB. Some in vitro and animal data suggest HDL cholesterol efflux may regulate platelet function and reduce the risk of thrombosis. It is unclear whether SG and RYGB affect platelets via their effects on cholesterol efflux. This knowledge will suggest potential mechanisms that may be assessed for intervention to reduce CV and thrombosis risk in both obese and non-obese individuals. To investigate the effect of SG and RYGB on platelet characteristics and function, and specifically post-bariatric surgery HDL on measures of platelet activity, this project will include both analysis of preserved biospecimens and a prospective study of obese patients undergoing bariatric surgery to thoroughly compare the effects of SG and RYGB on HDL-mediated cholesterol efflux in platelet function and gene expression. The specific aims are to: (1) identify mechanisms underlying differential effects of RYGB and SG on HDL function, (2) determine if bariatric surgery improves the ability of HDL to inhibit platelet activation and megakaryocyte inflammatory state, and (3) determine if surgical weight loss results in reduced platelet inflammation and activation in severe obesity. By using multiple approaches to explore a potential pathophysiologic link between obesity, HDL function, and thrombosis, these innovative studies will support a robust training plan in translational research in obesity and CVD, and promote the development of the PI into an independent translational physician-scientist.